COMPARISON OF LUNG INJURY DEVELOPMENT IN HCl-INDUCED ARDS FROM TWO DIFFERENT WILD TYPE MICE STRAIN
CCCF ePoster library. Grassi A. Oct 27, 2015; 117334; P74 Disclosure(s): CIHR
Dr. Alice Grassi
Dr. Alice Grassi
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Abstract
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P74


Topic: Basic/Translational Science


COMPARISON OF LUNG INJURY DEVELOPMENT IN HCl-INDUCED ARDS FROM TWO DIFFERENT WILD TYPE MICE STRAIN



Alice Grassi, H. Bing, A. Luo, M. Li, J. Zheng, D. Islam, A. Pesenti, A. Slutsky, H. Zhang

Anaesthesia, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Health Science Department, University of Milan-Bicocca, Toronto, Canada | Anaesthesia, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Anaesthesia, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Anaesthesia, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Department of Critical Care Medicine, The Second Affiliated hospital of Harbin Medical University,  Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Harbin, China | Anaesthesia, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, Toronto, Canada | Health Science, University of Milano Bicocca, Italy, Milan, Italy | Critical Care Medicine, Keenan Research Center for Biomedical Science of St. Michael’s Hospital, University of Toronto, Toronto, Canada | Anaesthesia, Keenan Research Center for Biomedical Science of St. Michael’s Hospital,  University of Toronto, Toronto, Canada

Introduction:

Acute respiratory distress syndrome (ARDS) is a leading cause of high mortality in the ICU. Recent studies have correlated the high mortality rate with the development of fibrotic responses in ARDS. Animal models have been widely used to examine the mechanisms of organ fibrosis by taking the advantage of using different genetic background of mice1. C57BL/6 mice are a strain commonly use for models of lung fibrosis2,3 while FVB/N mice show resistance to develop fibrosis in distal organs, such as liver4,5. We thus employed the C57BL/6 and FVB/N mice to investigate if they responded differently or not in the context of lung fibrosis development in an ARDS model. Our results would help one understand the mechanisms underlying the ARDS associated lung fibrosis.



Objectives:

FVB/N mice are more resistant to fibrosis development in HCl-induced lung injury in comparison to C57BL/6 mice.



Methods:

C57BL/6 and FVB/N mice were anaesthetized and randomized to receive HCl (3ml/kg, pH 1.0) or normal saline (NS) as vehicle controls. Mice were orotracheally intubated, received HCl/NS intratracheal instillation and were mechanically ventilated for 10 minutes for the distribution of the liquid in the lung. After weaning, the mice were housed and monitored for up to 7 days in the animal facility. Lung compliance and elastance were measured, blood and lung tissues were collected for analysis of inflammatory responses and lung fibrosis.



Results: There was a trend of increase in lung elastance in the C57BL/6 mice after HCl instillation(18.5±7.8 cmH2O vs 10.4±0.3 cmH2O at baseline, p=0.08), and this trend was not observed in the FVB/N mice. An increased myeloperoxydase (MPO) activity as a marker of neutrophil activation and higher levels of inflammatory cytokines (IL-6, and MCP-1) were seen in the C57BL/6 mice than in the FVB/N mice after HCl instillation. The C57BL/6 mice also showed an increased gene expression of collagen III mRNA as compared to the FVB/N mice in response to HCl challenge. However, the FVB/N mice exhibited a dominant acute response resulting in a higher mortality rate (35% vs. 0%, p<0.05) than the C57BL/6 mice in response to HCl instillation at 48 h.

Conclusion:

The FVB/N mice were more susceptible to the HCl-induced acute response leading to a high mortality rate, but were well recovered upon surviving from the acute phase of injury, while the C57BL/6 mice were more resistant at early stage in response to the HCl-induced lung injury. However, they developed greater inflammatory response and collagen deposition at late stages. Since FVB/N mice are lacking of complement C5, our results may suggest that a protective and a pro-fibrotic role of C5 may exist respectively in early and late ARDS stages.



References:

1 Walkin et al., The role of mouse strain differences in the susceptibility to fibrosis: a systematic review, Fibrogenesis& Tissue Repair, 2013

2 Cabrera-Benitez et al., Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition, Critical Care Medicine, 2012

3 Izbicky et al., Bleomycin-induced lung fibrosis in IL-4 overexpressing and knock out mice, Am J Physiol Lung Cell Molec Physiol, 2002

4 Hillebrandt et al., Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans, Nature Genetics, 2005

5 Bauer, Identification of new quantitative trait loci in mice with collagen-induced arthritis, Arthritis and Rheumatism, 2004

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